The major aims of this project have been accomplished through the establishment of a large community-based family study of adult probands who participate in comprehensive clinical and biologic assessments followed by comparable evaluations of their adult and child relatives. Recruitment of probands and evaluation of relatives are now near completion and analyses of the findings are underway. To date, we have enrolled 905 probands, 1388 relatives, and 175 children into the study from community, clinical, and other recruitment sources. Over 500 probands and about 1000 of their relatives have completed the study, of which 500 have been evaluated at the National Institutes of Health (NIH) Clinical Center. Probands represent a large range of disorders including mood, anxiety, sleep, migraine, and cardiovascular in addition to controls. We are now completing interviews with relatives who had not previously participated in the study. We have also begun to follow-up families in order to track health changes in child and adolescent relatives over time. In order to identify the core features of mood and anxiety disorders and their overlap with sleep problems, cardiovascular diseases and migraine, we have established a set of clinical, psychophysiological and neuropsychological measures. The comprehensive set of measures in the study are divided into three components: (1) clinical information that includes a semi-structured diagnostic interview for mood and anxiety disorders; structured diagnostic interviews for major headache syndromes and for sleep disorders; family history of psychiatric disorders, sleep disorders and headache syndromes, and a series of self-reported measures of symptoms, sleep patterns and personality; medical history, family structure, history and function, and major life and family events; (2) in person evaluation at the NIH Clinical Center that includes physical and neurological examination; autonomic nervous system evaluation using tilt and valsalva maneuver; laboratory measures of metabolic, cardiovascular, and immunologic function; psychophysiologic evaluation including startle reflex and eyeblink reflex; structural magnetic resonance imaging; a computerized cognitive assessment battery; and olfactory function; and (3) two-week assessment of daily activities including an electronic diary that assesses daily rhythms including mood, anxiety, sleep, stress, activity, diet, and social activities; heart rate reactivity using a holter monitor; activity and sleep using an actiwatch; and salivary hormones collected four times per day. In the past year, we have continued to run analyses on several of these clinical components and are working with external collaborators to design and implement analyses of all of the measures in the study. This study has yielded substantial methodological developments including the development and validation of a structured diagnostic interview for headache syndromes (Lateef et al, 2012); systematic assessment of the validity of the National Institute of Mental Health (NIMH) Family Study Diagnostic Interview for Affective Spectrum Disorders that was developed for this study compared to the Structured Clinical Interview for DSM-IV; and the validation of the NIMH Sleep Diagnostic Interview also developed for this study compared with sleep disorder diagnoses made by sleep experts (Merikangas et al, 2014). We also joined the Research Electronic Data Capture Consortium through Vanderbilt University and are in the process of transferring our study interviews and questionnaires into computerized databases for enhanced data collection and instrument sharing. We have completed the primary analyses of the familial aggregation of mood disorder subtypes, their patterns of comorbidity, and their co-aggregation in relatives, and have published the principal paper that reports these findings. Likewise, we have also completed analyses of the familial aggregation of migraine and comorbid conditions. The major findings confirm the familial aggregation of bipolar disorder and major depression that has been found in earlier family studies of mood disorders, but in a community-based sample that suspended diagnostic hierarchies of earlier diagnostic systems. The most important finding that emerged from this study is the independent familial transmission of mania and depression suggesting that these two mood states may represent distinct underlying diatheses. The lack of familial aggregation of hypomania suggests that the bipolar spectrum concept may not be a valid entity. We also found strong evidence for familial specificity of atypical depression in probands and interviewed relatives, thereby confirming the validity of this subtype of depression. Additional analyses that are currently being investigated include the familial aggregation of subtypes of sleep disorders, early manifestations of mood and anxiety disorders in offspring of parents with mood spectrum disorders, and heritability analyses of both disorders and underlying traits. During the last year, we have devoted substantial effort to completion of diagnostic reviews and conducting best estimate diagnoses of the interview and family history information in this study. We have conducted numerous analyses of the familial aggregation of subtypes of mood disorders, co-aggregation of temperament and disorders in families, and familial patterns of sleep disorders and their relationship with mood disorders. We have also completed initial analyses of the data from multiple domains of assessment including activity monitors, ecological momentary assessment, neuropsychological data, olfactory function, autonomic reactivity, potentiated startle and neuroimaging data. These analyses will be completed during the next project period and findings will be submitted for publication. Public Health Impact: Integration of the clinical, neuropsychological and psychophysiological measures within families will render an in-depth analysis of the biological mechanisms crucial for mood and anxiety disorders and their underlying diatheses. This will not only lead to a better understanding of these conditions and assist in identifying common genetic mechanisms, but may also lead to the development of novel treatment options and possible strategies for prevention and early intervention in those with elevated risk for these conditions. Future Plans: During the next project year, we plan to focus on follow-up of the families to complete enrollment of relatives. We will continue the evaluation of relatives, including increased enrollment of child and adolescent relatives who have not yet been enrolled in the study. We will continue to follow-up the probands and relatives currently enrolled in the study to update the diagnostic status and to continue the current biologic studies. We also plan to repeat the measures of circadian rhythms of activity, sleep and cognitive and mood states to test their stability through the use of mobile technologies. We will continue analyses of familial aggregation of mood disorders and anxiety disorders as well as the biologic and laboratory measures that were included in the study. Classification models will be employed to identify core underlying domains as indexed by the biomarker and clinical assessments now underway. Study measures will be refined to eliminate those measures that are not informative with respect to either mood disorders or familial aggregation. Based on the findings from analyses of the study, we plan to design and pilot interventions that stabilize regulation of activity, sleep and other daily rhythms in this and other samples.